We intend to continue our work on defining the active site of alpha-l-proteinase inhibitor in order to find a link between lung disease and smoking. We have found that an easily oxidizable methionyl residue forms a critical portion of the active site of this inhibitor and believe that cigarette smoke causes the same effect when inhaled into the lungs. The oxidation causes an immediate loss in inhibitory activity towards proteolytic enzymes resulting in proteolysis by enzymes such as leukocyte elastase which is the enzyme primarily inhibited by alpha-l-PI. We are also investigating the role of alpha-l-antichymotrypsin in controlling proteolysis by another important enzyme, referred to as cathepsin G, which is also present in high concentration in neutrophils.